ORGANIC LETTERS
Total Synthesis of Penostatin B Kosuke Fujioka, Hiromasa Yokoe, Masahiro Yoshida, and Kozo Shishido*
2012 Vol. 14, No. 1 244–247
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
[email protected] Received November 9, 2011
ABSTRACT
The first total synthesis of penostatin B has been accomplished by using a highly diastereoselective Pauson Khand reaction and an efficient relay ring-closing metathesis for the construction of the basic carbon skeleton of the natural product as the key steps.
Penostatins A (1) and B (2) are representatives of nine molecules in this family that have been isolated from a strain of Penicillium sp. originally separated from the marine alga Enteromorpha intestinalis by Numata and co-workers in 1996.1a Except for penostatin D, these polyketide-derived penostatins all exhibited significant cytotoxicity against cultured P388 cells.1 Their structures and absolute stereochemistry have been established on the basis of spectral analyses and chemical transformations. The penostatins A and B possess a synthetically challenging array of structural features: five tertiary stereogenic centers, a densely functionalized hexahydrocyclopenta[f]chromenone skeleton, and the fascinating sigma linkage at C12 (a skipped diene) (Figure 1). To date, although the synthesis of (()-5-deoxypenostatin A2 has been reported, none of the natural penostatins have been synthesized. Herein, we present the first total synthesis of (()penostatin B (2), employing as the key steps a highly (1) (a) Takahashi, C.; Numata, A.; Yamada, T.; Minoura, K.; Enomoto, S.; Konishi, K.; Nakai, M.; Matsuda, C.; Nomoto, K. Tetrahedron Lett. 1996, 37, 655–658. (b) Iwamoto, C.; Minoura, K.; Hagishita, S.; Nomoto, K.; Numata, A. J. Chem. Soc., Perkin Trans. 1 1998, 449–456. (c) Iwamoto, C.; Minoura, K.; Oka, T.; Hagishita, S.; Numata, A. Tetrahedron 1999, 55, 14353–14368. (2) Snider, B. B.; Liu, T. J. Org. Chem. 2000, 65, 8490–8498. (3) For a review, see: (a) Laschat, S.; Becheanu, A.; Bell, T.; Baro, A. Synlett 2005, 17, 2547–2570. (b) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett. 1990, 31, 5289–5292. (c) Chung, Y. K.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L. Organometallics 1993, 12, 220– 223. (d) Hoye, T. R.; Suriano, J. J. Org. Chem. 1993, 58, 1659–1660. (e) Mukai, C.; Kim, J. S.; Sonobe, H.; Hanaoka, M. J. Org. Chem. 1999, 64, 6822–6832. (f) Ishikawa, T.; Shimizu, K.; Ishii, H.; Ikeda, S.; Saito, S. J. Org. Chem. 2001, 66, 3834–3847. (g) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Angew. Chem., Int. Ed. 2011, 50, 8025– 8028. 10.1021/ol203021c r 2011 American Chemical Society Published on Web 12/06/2011
diastereoselective Pauson Khand reaction3 for the construction of the tetrahydroindenone segment, an efficient assembly of the dihydropyranone moiety using a relay ring-closing metathesis,4 and a diastereoselective introduction of the alkenyl appendage at C12 on the dihydropyran ring.
Figure 1. Penostatins A and B.
Our retrosynthetic strategy is illustrated in Scheme 1. We reasoned that the alkenyl side chain at C12 could be introduced at a late stage of the synthesis via a Lewis acid mediated alkenylation of the acetate 3. The dihydropyran moiety in 3 would be assembled via the ring-closing metathesis (RCM) protocol of the corresponding diene precursor, which can be readily derived from 4. The alkenyl alcohol 4 with four contiguous stereogenic centers would be constructed diastereoselectively by the Pauson Khand (4) (a) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210–10211. (b) Hoye, T. R.; Danielson, M. E.; May, A. E.; Zhao, H. J. Org. Chem. 2010, 75, 7052– 7060.
Scheme 1. Retrosynthetic Analysis
reaction of the dienyl alcohol 5,5 which in turn would be synthesized from the aldehyde 6 by metal-mediated diastereoselective pentadienylation.6 The aldehyde 6 can be prepared from the glycidyl ester 7,7 which is readily available in both racemic and optically active forms (Scheme 1). The aldehyde 6, prepared from (()-oxiran-2-ylmethyl butyrate 7 via a four-step sequence, was treated with (E)tributyl(penta-2,4-dienyl)stannane in the presence of InCl36 to give the pentadienylated alcohol 5 as a single product in 75% yield. The diastereoselectivity can be attributed to the indium-chelated chairlike transition state (T1) as shown in Scheme 2.
Table 1. Pauson Khand Reaction
entry
substrate
conditions
1
8
2
5
3
5
Co2(CO)8, CH2, rt, 8 h, then NMO, CH2Cl2, rt, 8 h Co2(CO)8, CH2, rt, 8 h, then NMO, CH2Cl2, rt, 8 h Co2(CO)8, CH2, rt, 8 h, then evaporation, add MeCN, 60 °C, 8 h
product (ratio)
yield (%)
9/10 (4/1)
72
4 (>20:1)
86
4 (>20:1)
97
NOE experiments, and it was determined that the major diastereoisomer 9 was indeed the desired product (Figure 2). When compound 5 was subjected to the same reaction conditions as those for 8, the bicycle 4 was produced in 86% yield as a single product (entry 2). A higher yield (97%) and complete diastereoselectivity of the product 4 were obtained under these conditions without an oxidizing agent (NMO) (entry 3).3c e
Scheme 2. Diastereoselective Synthesis of 5
Figure 2. NOE experiments.
We next examined the key Pauson Khand cyclization for the construction of the tetrahydroindenone segment with four contiguous stereogenic centers. To evaluate the diastereoselectivity of the cyclization, the desilylated compound 8 was prepared and its cyclizations were explored. The results are shown in Table 1. Sequential treatment of a solution of the desilylated substrate 8 in CH2Cl2 with Co2(CO)8 and N-methylmorpholine N-oxide (NMO),3b gave a chromatographically separable 4:1 mixture of the diastereoisomers 9 and 10, in 72% yield (entry 1). The stereostructures of both were determined by 1H NMR
The diastereoselective formation of the requisite tetrahydroindenone 4 can be explained by considering the conformation of the transition states T2 and T3 for the Pauson Khand reaction.8 In the transition state T3, leading to the formation of the undesired isomer 10, the R group on the cobalt complex moiety interacts with an axially oriented vinyl group so that the substrate 5 with a bulkier substituent (R = TMS) resulted in the exclusive formation of the desired bicycle 4 via T2 (Scheme 3). After desilylation, the enone double bond in 4 was selectively reduced with DIBAH/MeLi in the presence of CuI in HMPA/THF9 to give 11, which was condensed with methacrylic acid in the presence of 2-methyl-6-nitrobenzoic
(5) Magnuson, S. R. Tetrahedron 1995, 51, 2167–2213. (6) Nishigaichi, Y.; Hanano, Y.; Takuwa, A. Chem. Lett. 1998, 33–34. (7) Trost, B. M.; Papillon, P. N.; Nussbaumer, T. J. J. Am. Chem. Soc. 2005, 127, 17921–17937.
(8) Magnus, P.; Principe, L. W. Tetrahedron Lett. 1985, 26, 4851– 4854. (9) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J. Org. Chem. 1986, 51, 537–540.
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Scheme 3. Plausible Mechanism of Pauson Khand Reaction
anhydride (MNBA)10 to provide 13 in excellent yield (Scheme 4).
Table 2. Attempted Ring-Closing Metathesis of 13
entry
catalyst (mol %)
1 2 3 4
15 (15) 15 (25) 16 (10) 15 (5)
additive
time (h)
yield (%)a
Ti(OiPr)4
32 8 32 6
11 (61) 47 (77) 0 (75) b
a The yield in parentheses is the yield based on the recovered starting material. b The compound 17 was obtained in 46% yield.
Scheme 4. Synthesis of the Substrate 13 for RCM
21, prepared from 19. Thus, compound 21 was treated with 25 mol % of 15 in refluxing CH2Cl2 to give 14 in 83% yield. Thus, it was demonstrated that RRCM is a versatile method to obtain the functionalized dihydropyranones (Scheme 5).14 With the diene 13 in hand, we next examined the RCM for assembling the dihydropyranone ring in 14.11,12 Treatment of 13 with the Grubbs’ second-generation catalyst 15 (15 mol %) in refluxing CH2Cl2 for 32 h provided only 14 in 11% yield (61% based on the recovered starting 13) (entry 1, Table 2). When the reaction was conducted using 25 mol % of 15, compound 14 was obtained in moderate yield (47%; 77% brsm) (entry 2). Using the Grubbs Hoveyda catalyst 16 or 15 and Ti(OiPr)411 resulted in no reaction (entry 3) or the formation of 1713 in 46% yield (entry 4). In an effort to improve the lower yield of 14, we decided to use a relay ring-closing metathesis (RRCM).4 Treatment of 11 with the carboxylic acid 18, prepared from allyl alcohol via four steps, in the presence of MNBA 12, triethylamine, and DMAP provided the ester 20 in 93% yield. When 20 was exposed to 50 mol % of 15 in refluxing CH2Cl2, 14 was produced in 78% yield. Much better results were obtained when the RRCM was conducted with the methyl homologue (10) Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002, 286–287. (11) For a review, see: (a) Monfette, S.; Fogg, D. F. Chem. Rev. 2009, 109, 3783–3816. (b) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2007, 18, 2479–2483. (c) Pospı´ sil, J.; Mark o, I. E. Tetrahedron Lett. 2008, 49, 1523–1526. (12) (a) F€ urstner, A.; Langeman, K. J. Am. Chem. Soc. 1997, 119, 9130–9136. (b) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651–4654. (c) Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron Lett. 1999, 40, 4187–4188. (13) Schmidt, B. Eur. J. Org. Chem. 2004, 1865–1880. 246
Scheme 5. Relay Ring-Closing Metathesis
Having made the construction of the basic carbon framework, we next examined the introduction of the alkenyl appendage at C12. Reduction of 14 with DIBAH (87%) followed by acetylation provided the diacetate 22, as a mixture of diastereoisomers, which was treated with the vinyl stannane 2315 in the presence of BF3•OEt2 to provide 24, as an inseparable 9:1 mixture of diastereoisomers at C5, in 74% (two steps from the diol). (14) Druais, V.; Hall, M. J.; Corsi, C.; Wendeborn, S. V.; Meyer, C.; Cossy, J. Tetrahedron 2010, 66, 6358–6375. (15) Amans, D.; Beronique, V.; Cossy, J. Org. Lett. 2007, 9, 4761–4764. Org. Lett., Vol. 14, No. 1, 2012
The stereochemistry at C12 was established by NOE experiments as shown in Scheme 6.
Scheme 6. Diastereoselective Alkenylation
in the literature. The unique features of this work include the use of a highly diastereoselective indium-mediated pentadienylation and intramolecular Pauson Khand cyclization, the successful application of an efficient RRCM for assembling the dihydropyranone moiety, and the diastereoselective introduction of the C9 alkenyl side chain at C12. The synthetic route developed here is general and efficient and could also be applied to the syntheses of other penostatins.
Scheme 7. Total Synthesis of Penostatin B (2)
Alkaline hydrolysis of 24 followed by silylation provided the TBS ether 25 in 89% in two steps, and at this stage the minor diastereoisomer with the 5R* configuration could be separated. Debenzylation using LiDBB/MgBr2•OEt216 proceeded smoothly to give the alcohol, which was oxidized with TPAP/NMO in the presence of 4A MS to provide the ketone 26 in excellent yield. Finally, the Ito Saegusa oxidation,17 followed by desilylation of the TBS ether with HF•pyridine, provided (()-penostatin B (2) in 53% yield. The 1 H and 13C NMR properties of the synthetic material were identical with those of the natural penostatin B1 (Scheme 7). In summary, we have completed the first total synthesis of penostatin B in a longest linear sequence of 16 steps with an overall yield of 12% from compound 6, which is known (16) Fukuda, K.; Miyashita, M.; Tanino, K. Tetrahedron Lett. 2010, 51, 4523–4525. (17) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
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Acknowledgment. We thank Emeritus Professor Atsushi Numata (Osaka University of Pharmaceutical Sciences) for kindly providing us copies of 1H and 13C NMR of penostatin B. A Grant-in-Aid Fellowship was given to H.Y. from the JSPS for JSPS Fellows (20-11673). This work was supported financially by a Grant-in-Aid for the Program for Promotion of Basic and Applied Research for Innovations in the Bio-oriented Industry (BRAIN). Supporting Information Available. Experimental pro cedures and characterization data for the new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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